The present invention relates to a novel aromatic nitrogen containing 6-membered cyclic compound exhibiting a cGMP specific phosphodiesterase (PDE) inhibitory activity (PDE V inhibitory activity) and being useful as a medicament, and a process for preparing the same.
In general, it is known that cGMP, which is an intracellular second messenger, is decomposed and inactivated by phosphodiesterase which widely distributes in many cell types and tissues of the living body, and when said PDE activity is inactivated, the level of cGMP in cells is increased, and as a result, various pharmacological activities, for example, relaxation of vascular smooth muscle, relaxation of bronchial smooth muscle, and inhibition of platelet aggregation are exhibited.
Moreover, it has been reported that such cGMP specific PDE inhibitors (i.e., PDE V inhibitors) are useful in the treatment of diseases caused by a functional disorder of cGMP-signaling, including hypertension, angina pectoris, myocardial infarction, chronic or acute heart failure, pulmonary hypertension, etc. (cf., PCT Patent Publication WO 96/05176, etc.), and prostatic hyperplasia (Australian Patent Publication No. 9955977). It has also been reported that PDE V inhibitors may be useful in the treatment of female sexual dysfunction (Vemulapalli et al., Life Sciences, 67, 23-29 (2000)), diabetic gastroparesis (Watkins et al., J. Clin. Invest. 106: 373-384 (2000)), achalasia (Bortolotti et al., Gastroenterology; 118: 253-257 (2000)), diarrhea (Mule et al., Br. J. Pharmacol., 127, 514-520 (1999)), constipation (Bakre et al., J. Cell. Biochem. 77: 159-167 (2000)) and asthma (Turner et al., Br. J. Pharmacol., 111, 1198-1204 (1994)).
Furthermore, it has been also reported that 1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d]pyrimidin-5-yl)phenylsulfonyl]-4-methylpiperazine [general name: Sildenafil] having PDE V inhibitory activity is useful in the treatment of diseases such as penile erectile dysfunction (copulative impotence), etc. (cf., Boolell et al., The Journal of Urology, Supplement, vol. 155, no. 5, p. 495A739 (1996); Terrett et al., Bioorganic and Medicinal Chemistry Letters, vol. 6, no. 15, p. 1819 (1996); and Ballard et al., British Journal of Pharmacology, Proceeding Supplement, vol. 118, p. 153 (1996)).
However, sildenafil has been reported to have side effects such as headache, facial suffusion, gut disorder, rhinitis, color sense disorder, penile erectile continuance, etc. (Irwin et al., The New England Journal of Medicine, vol. 338, no. 20, p. 1397-1404 (1998); Morales et al., International Journal of Impotence Research, vol. 10, no. 2, p. 69-73 (1998); and Goldenberg, Clinical Therapeutics, vol. 20, no. 6, p. 1033-1048 (1998)).
In addition, sildenafil has also been reported that the effects of sildenafil on light response of retina tissues and its PDE VI inhibitory activity correlate each other in the experiments on dogs (Morales et al., International Journal of Impotence Research, vol. 10, no. 2, p. 69-73 (1998)), while it has been reported that PDE VI on retina plays an importance role in the sensation of light (Morrales et al., International Journal of Impotence Research, vol. 10, no. 2, p. 69-73 (1998); Estrade et al., European Journal of Pharmacology, vol. 352, p. 157-163 (1998)).
An object of the present invention is to provide a novel aromatic nitrogen-containing 6-membered cyclic compound showing an excellent phosphodiesterase V (PDE V) inhibitory activity, and being useful as a remedy for the prophylaxis or treatment of penile erectile dysfunction with few side effects. Another object of the present invention is to provide a process for preparing such a novel aromatic nitrogen-containing 6-membered cyclic compound.
The present invention relates to an aromatic nitrogen-containing 6-membered cyclic compound of the formula (I): 
wherein Ring A is a substituted or unsubstituted nitrogen-containing heterocyclic group; R1 is a substituted or unsubstituted lower alkyl group, a group of the formula: xe2x80x94NHxe2x80x94Qxe2x80x94R3 (in which R3 is a substituted or unsubstituted nitrogen-containing heterocyclic group, and Q is a lower alkylene group or a single bond), or a group of the formula: xe2x80x94NHxe2x80x94R4 (in which R4 is a substituted or unsubstituted cycloalkyl group); R2 is a substituted or unsubstituted aryl group; one of Y and Z is a group of the formula: xe2x95x90CHxe2x80x94, and the other is a group of the formula: xe2x95x90Nxe2x80x94, or a pharmaceutically acceptable salt thereof, and a process for preparing the same.
Among the compounds (I) of the present invention, the nitrogen-containing heterocyclic group of the xe2x80x9csubstituted or unsubstituted nitrogen-containing heterocyclic groupxe2x80x9d for Ring A is a 5- to 10-membered monocyclic or bicyclic nitrogen-containing heterocyclic group, more particularly, a 5- or 6-membered nitrogen-containing heteromonocyclic group and a 8- to 10-membered nitrogen-containing heterobicyclic group, and most particularly, a 5- or 6-membered non-aromatic nitrogen-containing heteromonocyclic group such as pyrrolidinyl group, piperazinyl group, piperidyl group, morpholino group, etc., a 5- or 6-membered aromatic nitrogen-containing heteromonocyclic group such as imidazolyl group, pyrrolyl group, etc., and a nitrogen-containing heterobicyclic group such as 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl group, 5,6,7,8-tetrahydroimidazo[1,2-a]-pyrazin-7-yl group, 5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl group, 1,2,3,4-tetrahydro-2-isoquinolinyl group, 1H-2,3,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl group, 4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-6-yl group, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl group, 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl group, etc.
The nitrogen-containing heterocyclic group of the xe2x80x9csubstituted or unsubstituted nitrogen-containing heterocyclic groupxe2x80x9d for R3 is a 5- or 6-membered nitrogen-containing heteromonocyclic group or a 8- to 10-membered nitrogen-containing heterobicyclic group, for example, a 5- or 6-membered non-aromatic nitrogen-containing heteromonocyclic group such as morpholinyl group, piperazinyl group, piperidyl group, thiadiazolyl group, dihydropyrimidinyl group, dihydropyrazolyl group, a 5- or 6-membered aromatic nitrogen-containing heteromonocyclic group such as pyrimidinyl group, pyridazinyl group, pyridyl group, pyrazolyl group, imidazolyl group, oxazolyl group, thiazolyl group, pyrazinyl group, and a 8- to 10-membered nitrogen-containing heterobicyclic group such as benzothiazolyl group, quinolyl group, dihydrobenzoxazolyl group, etc.
The substituent of the xe2x80x9csubstituted or unsubstituted nitrogen-containing heterocyclic groupxe2x80x9d for Ring A and R3 is, for example, (1) a lower alkyl group, (2) a hydroxy-substituted lower alkyl group, (3) a formyl group, (4) an oxo group, (5) an amino group, (6) a di-(lower alkyl)amino group, (7) a hydroxy group, (8) a lower alkoxy group, (9) a lower alkoxycarbonyl group, (10) a lower alkoxy-substituted lower alkanoyl group, (11) a lower alkanoyl group, (12) a cyano-substituted lower alkyl group, and (13) a pyrimidinyl group substituted by (i) a benzylamino group substituted by a halogen atom and a lower alkoxy group and (ii) a cycloalkylcarbamoyl group substituted by a hydroxy group, etc.
The aryl group of the xe2x80x9csubstituted or unsubstituted aryl groupxe2x80x9d for R2 is, for example, a 5- to 10-membered monocyclic or bicyclic aromatic hydrocarbon group such as phenyl group, naphthyl group, etc.
The substituent of the xe2x80x9csubstituted or unsubstituted aryl groupxe2x80x9d for R2 is, for example, a lower alkoxy group, a halogen atom, a cyano group, a nitro group, a hydroxy group, a lower alkyl group, etc.
The substituent of the xe2x80x9csubstituted or unsubstituted lower alkyl groupxe2x80x9d for R1 and the substituent of the xe2x80x9csubstituted or unsubstituted cycloalkyl groupxe2x80x9d for R4 are, for example, a lower alkoxy group, a hydroxy group, a morpholinyl group, a lower alkylsulfonyl group, a di-(lower alkyl)phosphino group, a di-(lower alkyl)amino group, a pyrimidinyl-substituted lower alkylamino group, a pyridyl group, a pyridylamino group, a lower alkyl-substituted piperazinyl group, a pyrimidinyloxy group, etc.
Throughout the present description and the claims, the xe2x80x9clower alkyl groupxe2x80x9d means a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc. The xe2x80x9clower alkoxy groupxe2x80x9d means a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy, etc.
The xe2x80x9ccycloalkyl groupxe2x80x9d means a cycloalkyl having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The xe2x80x9clower alkylene groupxe2x80x9d means a straight chain or branched chain alkylene group having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, etc.
The xe2x80x9chalogen atomxe2x80x9d means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
Among the compounds (I) of the present invention, preferable compounds are compounds of the formula (I) wherein the nitrogen-containing heterocyclic group of the xe2x80x9csubstituted or unsubstituted nitrogen-containing heterocyclic groupxe2x80x9d for Ring A is a 5- or 6-membered nitrogen-containing heteromonocyclic group or a 8- to 10-membered nitrogen-containing heterobicyclic group, and the substituent of the above xe2x80x9csubstituted or unsubstituted nitrogen-containing heterocyclic groupxe2x80x9d is selected from the group consisting of (1) a lower alkyl group, (2) a hydroxy-substituted lower alkyl group, (3) a formyl group, (4) an oxo group, (5) an amino group, (6) a hydroxy group, (7) a lower alkoxycarbonyl group, and (8) a pyrimidinyl group substituted by (i) a benzylamino group substituted by a halogen atom and a lower alkoxy group and (ii) a cycloalkylcarbamoyl group substituted by a hydroxy group, R1 is a lower alkyl group which may optionally be substituted by a group selected from the group consisting of a lower alkoxy group, a hydroxy group, a morpholinyl group, a lower alkylsulfonyl group, a di-(lower alkyl)phosphino group, a di-(lower alkyl)amino group, a pyrimidinyl-substituted lower alkylamino group, a pyridyl group, a pyridylamino group, and a lower alkyl-substituted piperazinyl group, a group of the formula: xe2x80x94NHxe2x80x94Qxe2x80x94R3, or a group of the formula: xe2x80x94NHxe2x80x94R4, the nitrogen-containing heterocyclic group of the xe2x80x9csubstituted or unsubstituted nitrogen-containing heterocyclic groupxe2x80x9d for R3 is a 5- or 6-membered nitrogen-containing heteromonocyclic group or a 8- to 10-membered nitrogen-containing heterobicyclic group, and the substituent of the above xe2x80x9csubstituted or unsubstituted nitrogen-containing heterocyclic groupxe2x80x9d is selected from the group consisting of a lower alkyl group, a hydroxy-substituted lower alkyl group, an oxo group, an amino group, a di-(lower alkyl)amino group, a lower alkanoyl group and a cyano-substituted lower alkyl group, R4 is a cycloalkyl group being substituted by a group selected from the group consisting of hydroxy group, a lower alkoxy group and a pyrimidinyloxy group, R2 is a phenyl group being substituted by a group selected from the group consisting of a lower alkoxy group, a halogen atom, a cyano group, a nitro group, a hydroxy group and a lower alkyl group.
More particularly, preferable compounds of the present invention are compounds of the formula (I), wherein the nitrogen-containing heterocyclic group of the xe2x80x9csubstituted or unsubstituted nitrogen-containing heterocyclic groupxe2x80x9d for Ring A is a 5- or 6-membered nitrogen-containing heteromonocyclic group of the formula: 
or a nitrogen-containing heterobicyclic group of the following formula wherein the above-mentioned 5- or 6-membered nitrogen-containing heteromonocyclic group and a 5- or 6-membered cyclic group are fused: 
and the nitrogen-containing heterocyclic group of the xe2x80x9csubstituted or unsubstituted nitrogen-containing heterocyclic groupxe2x80x9d for R3 is a non-aromatic nitrogen-containing heteromonocyclic group of the formula: 
or an aromatic nitrogen-containing heterocyclic group of the formula: 
Among the compounds (I) of the present invention, other preferable compounds are compounds of the formula (I) wherein the nitrogen-containing heterocyclic group of the xe2x80x9csubstituted or unsubstituted nitrogen-containing heterocyclic groupxe2x80x9d for Ring A is a 5- or 6-membered nitrogen-containing heteromonocyclic group or a 8- to 10-membered nitrogen-containing heterobicyclic group, and the substituent of the above xe2x80x9csubstituted or unsubstituted nitrogen-containing heterocyclic groupxe2x80x9d is selected from the group consisting of a lower alkyl group, a hydroxy-substituted lower alkyl group, a formyl group and an oxo group, R1 is a lower alkyl group which may optionally be substituted by a group selected from the group consisting of a lower alkoxy group and a morpholinyl group, a group of the formula: xe2x80x94NHxe2x80x94Qxe2x80x94R3, or a group of the formula: xe2x80x94NHxe2x80x94R4, the xe2x80x9csubstituted or unsubstituted nitrogen-containing heterocyclic groupxe2x80x9d for R3 is a 5- or 6-membered nitrogen-containing heteromonocyclic group which may optionally be substituted by a lower alkyl group, R4 is a cycloalkyl group being substituted by a group selected from the group consisting of hydroxy group and a lower alkoxy group, R2 is a phenyl group being substituted by a group selected from the group consisting of a lower alkoxy group, a halogen atom and a cyano group.
More particularly, preferable compounds of the present invention are compounds of the formula (I) wherein the nitrogen-containing heterocyclic group of the xe2x80x9csubstituted or unsubstituted nitrogen-containing heterocyclic groupxe2x80x9d for Ring A is a 5- or 6-membered non-aromatic nitrogen-containing heteromonocyclic group of the formula: 
or a nitrogen-containing heterobicyclic group of the following formula wherein the above-mentioned 5- or 6-membered non-aromatic nitrogen-containing heteromonocyclic group and a 5- or 6-membered aromatic nitrogen-containing heteromonocyclic group are fused: 
the nitrogen-containing heterocyclic group of the xe2x80x9csubstituted or unsubstituted nitrogen-containing heterocyclic groupxe2x80x9d for R3 is a non-aromatic nitrogen-containing heteromonocyclic group of the formula: 
or an aromatic nitrogen-containing heteromonocyclic group of the formula: 
More particularly, preferable compounds of the present invention are compounds of the formula (I) wherein Ring A is a group of the formula: 
R1 is a lower alkyl group, a lower alkoxy-substituted lower alkyl group, a morpholinyl-substituted lower alkyl group, a group of the formula: xe2x80x94NHxe2x80x94Qxe2x80x94R3, or a group of the formula: xe2x80x94NHxe2x80x94R4, R3 is a group of the formula: 
R4 is a group of the formula: 
and R2 is a group of the formula: 
Among the compounds (I) of the present invention, more preferable compounds are compounds of the formula (I) wherein the nitrogen-containing heterocyclic group of the xe2x80x9csubstituted or unsubstituted nitrogen-containing heterocyclic groupxe2x80x9d for Ring A is a 5- or 6-membered nitrogen-containing heteromonocyclic group or a 8- to 10-membered nitrogen-containing heterobicyclic group, and the substituent of the above xe2x80x9csubstituted or unsubstituted nitrogen-containing heterocyclic groupxe2x80x9d is a group selected from the group consisting of a lower alkyl group, a hydroxy-substituted lower alkyl group, a formyl group and an oxo group, R1 is a lower alkoxy-substituted lower alkyl group, a group of the formula: xe2x80x94NHxe2x80x94Qxe2x80x94R3, or a group of the formula: xe2x80x94NHxe2x80x94R4, the xe2x80x9csubstituted or unsubstituted nitrogen-containing heterocyclic groupxe2x80x9d for R3 is a 5- or 6-membered nitrogen-containing heteromonocyclic group which may optionally be substituted by a lower alkyl group, R4 is a hydroxy-substituted cycloalkyl group, and R2 is a phenyl group being substituted by a group selected from the group consisting of a lower alkoxy group and a halogen atom.
More particularly, more preferable compounds of the present invention are compounds of the formula (I) wherein the nitrogen-containing heterocyclic group of the xe2x80x9csubstituted or unsubstituted nitrogen-containing heterocyclic groupxe2x80x9d for Ring A is a 5- or 6-membered non-aromatic nitrogen-containing heteromonocyclic group of the formula: 
or a group of the formula: 
the nitrogen-containing heterocyclic group of the xe2x80x9csubstituted or unsubstituted nitrogen-containing heterocyclic groupxe2x80x9d for R3 is a non-aromatic nitrogen-containing heteromonocyclic group of the formula: 
or
an aromatic nitrogen-containing heteromonocyclic group of the formula: 
More particularly, more preferable compounds of the present compounds are compounds of the formula (I) wherein Ring A is a group of the formula: 
R1 is a lower alkoxy-substituted lower alkyl group, a group of the formula: xe2x80x94NHxe2x80x94Qxe2x80x94R3, or a group of the formula: xe2x80x94NHxe2x80x94R4, R3 is a group of the formula: 
R4 is a group of the formula: 
and R2 is a group of the formula: 
Among the compounds (I) of the present invention, further preferable compounds are compounds of the formula (I) wherein the nitrogen-containing heterocyclic group of the xe2x80x9csubstituted or unsubstituted nitrogen-containing heterocyclic groupxe2x80x9d for Ring A is a 5- or 6-membered nitrogen-containing heteromonocyclic group or a 8- to 10-membered nitrogen-containing heterobicyclic group, and the substituent of the above xe2x80x9csubstituted or unsubstituted nitrogen-containing heterocyclic groupxe2x80x9d is a hydroxy-substituted lower alkyl group, R1 is a group of the formula: xe2x80x94NHxe2x80x94Qxe2x80x94R3, the xe2x80x9csubstituted or unsubstituted nitrogen-containing heterocyclic groupxe2x80x9d for R3 is a 5- or 6-membered nitrogen-containing heteromonocyclic group which may optionally be substituted by a lower alkyl group, and R2 is a phenyl group being substituted by a group selected from the group consisting of a lower alkoxy group and a halogen atom.
More particularly, the more preferable compounds of the present invention are compounds of the formula (I) wherein the nitrogen-containing heterocyclic group of the xe2x80x9csubstituted or unsubstituted nitrogen-containing heterocyclic groupxe2x80x9d for Ring A is a 5- or 6-membered non-aromatic nitrogen-containing heteromonocyclic group of the formula: 
or
a group of the formula: 
the nitrogen-containing heterocyclic group of the xe2x80x9csubstituted or unsubstituted nitrogen-containing heterocyclic groupxe2x80x9d for R3 is a non-aromatic nitrogen-containing heteromonocyclic group of the formula: 
or
an aromatic nitrogen-containing heteromonocyclic group of the formula: 
More particularly, the preferable compounds of the present invention are compounds of the formula (I), wherein Ring A is a group of the formula: 
R1 is a group of the formula: xe2x80x94NHxe2x80x94Qxe2x80x94R3, R3 is a group of the formula: 
and R2 is a group of the formula: 
Among the compounds (I) of the present invention, the most preferable compounds are compounds of the formula (I) wherein Y is a group of the formula: xe2x95x90Nxe2x80x94, and Z is a group of the formula: xe2x95x90CHxe2x80x94.
Among the compounds (I) of the present invention, pharmaceutically preferable compounds are compounds selected from the following group or a pharmaceutically acceptable salt thereof.
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine;
2-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl)-4-(3-cyano-4-methoxybenzylamino) -5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine:
2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(trans-4-methoxycyclohexyl)carbamoyl]pyrimidine;
2-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl)-4-(3-cyano-4-methoxybenzylamino) -5-[N-(trans-4-hydroxycyclohexyl)carbamoyl]pyrimidine;
2-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl)-4-(3-cyano-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;
2-[(2S)-2-hydroxymethyl-1-pyrrolidinyl]-4-(3-chloro-4-methoxybenzylamino)-5-[N-[[(2R)-4-methyl-2-morpholinyl]methyl]carbamoyl]pyrimidine;
2-[(2S)-2-hydroxymethyl-1-pyrrolidinyl]-4-(3-chloro-4-methoxybenzylamino)-5-[N-[[(2S)-4-methyl-2-morpholinyl]methyl]carbamoyl]pyrimidine;
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(4-pyrimidinylmethyl)carbamoyl]pyrimidine;
2-(4-methyl-3-oxo-1-piperazinyl)-4-(3-chloro-4-methoxybenzyl-amino)-5-[N-(trans-4-hydroxycyclohexyl)carbamoyl]pyrimidine;
2-(4-formyl-1-piperazinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(trans-4-hydroxycyclohexyl)carbamoyl]pyrimidine;
2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(trans-4-hydroxycyclohexyl)carbamoyl]pyrimidine;
2-[cis-2,5-bis(hydroxymethyl)-1-pyrrolidinyl]-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine;
2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine;
2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;
2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-acethylpyrimidine;
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(4-pyridazinylmethyl)carbamoyl]pyrimidine;
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(5-pyrimidinylmethyl)carbamoyl]pyrimidine;
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyridylmethyl)carbamoyl]pyrimidine;
(S)-2-[N-(2-pyrimidinylmethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-[2-hydroxymethyl-1-pyrrolidinyl]pyrazine;
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[(2-morpholinoethyl)carbonyl]pyrimidine;
2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-[(4-methyl-2-morpholinyl)methyl]-carbamoyl]pyrimidine;
(S) -2-[N-(2-morpholinoethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1pyrrolidinyl)pyrazine;
2-[N-(2-pyrimidinylmethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)pyrazine;
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[(2-methoxyethyl)carbonyl]pyrimidine;
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl]pyrimidine; or a pharmaceutically acceptable salt thereof.
Among the compounds (I) of the present invention, pharmaceutically more preferable compounds are compounds selected from the following group or a pharmaceutically acceptable salt thereof.
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine;
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(4-pyrimidinylmethyl)carbamoyl]pyrimidine;
2-(4-methyl-3-oxo-1-piperazinyl)-4-(3-chloro-4-methoxybenzyl-amino)-5-[N-(trans-4-hydroxycyclohexyl)carbamoyl]pyrimidine;
2-(4-formyl-1-piperazinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(trans-4-hydroxycyclohexyl)carbamoyl]pyrimidine;
2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine;
2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;
2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(5-pyrimidinylmethyl)carbamoyl]pyrimidine;
(S)-2-[N-(2-pyrimidinylmethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine;
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[(2-methoxyethyl)carbonyl]pyrimidine;
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl]pyrimidine; or a pharmaceutically acceptable salt thereof.
Among the compounds (I) of the present invention, pharmaceutically preferable other compounds are compounds selected from the following group or a pharmaceutically acceptable salt thereof.
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine;
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;
2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-2-pyrimidinylmethyl)carbamoyl]pyrimidine;
2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine;
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(5-pyrimidinylmethyl)carbamoyl]pyrimidine;
(S)-2-[N-(2-pyrimidinylmethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine;
(S)-2-[N-(2-morpholinoethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine;
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl]pyrimidine, or a pharmaceutically acceptable salt thereof.
Among the compounds (I) of the present invention, especially pharmaceutically preferable compounds are compounds selected from the following group or a pharmaceutically acceptable salt thereof.
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine, or a pharmaceutically acceptable salt thereof, 2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine, or a pharmaceutically acceptable salt thereof; and further (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(1,3,5-trimethyl-4pyrazolyl)carbamoyl]pyrimidine, or a pharmaceutically acceptable salt thereof.
When the compound (I) of the present invention or a pharmaceutically acceptable salt thereof has an asymmetric carbon atom at Ring A, R1 and/or R2, it may exist in the form of an optically active isomer thereof owing to said asymmetric carbon atom thereof, and the present invention also includes these optical isomers and a mixture thereof.
The compound (I) of the present invention or a pharmaceutically acceptable salt thereof exhibits an excellent selective PDE V inhibitory activity but substantially shows few side effects such as color sense disorder, and hence, it can be used in the prophylaxis or treatment of penile erectile dysfunction.
The present compound (I) can clinically be used either in the free form or in the form of a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt of the compound (I) includes a salt with an inorganic acid such as hydrochloride, sulfate, nitrate or hydrobromide, or a salt with an organic acid such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate, or maleate.
The present compound (I) or a salt thereof includes either intramolecular salt or an additive thereof, and solvates or hydrates thereof.
The present compound (I) or a pharmaceutically acceptable salt thereof can be administered either orally or parenterally, and can be formulated into a conventional pharmaceutical preparation such as tablets, granules, fine granules, pills, capsules, powders, injections, inhalants, buccal preparation, sublingual tablets, syrups, dry syrups, jellys, suppositories, ointments, elixirs, liniments, lotions, drinks, nasal drops, percutaneous preparations, and rapidly-disintegrating tablets in oral cavity, etc. These pharmaceutical preparations may be prepared by formulating with a pharmaceutically acceptable additive such as excipient, binder, wetting agent, disintegrator, thickening agent, etc., by a conventional method.
The dose of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof may vary in accordance with the administration routes, and the ages, weights and conditions of the patients. For example, when administered in an injection preparation, it is usually in the range of about 0.001-100 mg/kg/day, preferably in the range of about 0.1-10 mg/kg/day. When administered in an oral preparation, it is usually in the range of about 0.1-200 mg/kg/day, preferably in the range of about 0.1-80 mg/kg/day.
Concomitantly, since the compound (I) of the present invention or a pharmaceutically acceptable salt thereof exhibits an excellent selective PDE V inhibitory activity, it also may be useful in the prophylaxis or treatment of diseases caused by a functional disorder of cGMP-signaling, such as pulmonary hypertension, diabetic gastroparesis, hypertension, angina pectoris, myocardial infarction, chronic or acute heart failure, female sexual dysfunction, prostatic hyperplasia, asthma, diarrhea, constipation and achalasia in addition to the above-mentioned erectrile dysfunction.